PROJECT SUMMARY/ABSTRACT Newly formed memories are fragile and need to go through a process before they become stabilized and resistant to interference. This process is known as memory consolidation that takes days, weeks or even longer. Therefore, multiple memory traces are inevitably consolidated in parallel, as animals continuously form new memories of everyday life. However, it is unclear how memory specificity is maintained during the consolidation process. The current proposal aims to directly address how recently formed episodic memories are properly consolidated, and how dysregulated consolidation processes result in intermixed or overgeneralized memories. Converging evidence suggests that hippocampal sharp-wave ripple activity, which primarily occurs during slow-wave sleep and immobility, is critical for consolidation of episodic memory. Ripple activity refers to a fast (~200 Hz) field oscillation and is believed to be associated with reactivation of the recently formed memories. Growing studies support the notion that hippocampal ripples communicate with the neocortex including the anterior cingulate cortex (ACC) for transformation of short-term memory (hippocampus-dependent) into long- term memory (neocortex-dependent). We recently discovered that a subcortical region, the median raphe (MnR), plays a key role in regulation of hippocampal ripple activity and likely the ripple?ACC information exchange. A distinct population of MnR neurons increases firing at the termination of ripple events and pauses future ripple occurrence for regulation of the consolidation process. The central objective of this study is to test our hypothesis that MnR activity prevents different memories from intermixing by separating ripples, as well as ripple?ACC exchanged contents during the consolidation process. Supported by considerable preliminary data, we propose to pursue this objective through the following three specific aims. Aim 1 investigates the identity of the MnR neurons that regulate hippocampal ripple activity. Aim 2 investigates how physiological MnR activity regulates information exchange between the hippocampus and ACC, and how disrupted MnR activity may lead to intermixed memory associated with distinct contexts and emotions. Aim 3 investigates if the ACC sends feedback signals to the hippocampus via the MnR for regulation of memory consolidation. Results from this study will advance our understanding of memory formation associated circuits, and notably, reveal a new MnR?hippocampus?ACC circuitry for controlling memory specificity during consolidation. This could provide insight for improvement of memory and intervention into overgeneralized memory disorders such as the post-traumatic stress disorder (PTSD).